Key roles of necroptotic factors in promoting tumor growth
// Xinjian Liu 1, 2 , Min Zhou 1, 3 , Ling Mei 4, 5, 6, 7 , Jiaying Ruan 4, 5, 6, 7 , Qian Hu 4, 5, 6, 7 , Jing Peng 4, 5, 6, 7 , Hang Su 4, 5, 6, 7 , Hong Liao 4, 5, 6, 7 , Shanling Liu 4, 5, 6 , WeiPing Liu 8 , He Wang 4, 5, 6 , Qian Huang 2 , Fang Li 1 , Chuan-Yuan Li 1, 9 1 Department of Dermatology, Duke University Medical Center, Durham, North Carolina 27710, USA 2 Cancer Center, Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 201620, China 3 State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200032, China 4 Department of Obstetrics & Gynecology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China 5 MOE Key Laboratory of Obstetric & Gynecologic and Pediatric Diseases and Birth Defects, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China 6 Laboratory of Cell and Gene Therapy, West China Institute of Women and Children’s Health, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China 7 Laboratory of Genetics, West China Institute of Women and Children’s Health, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China 8 Department of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China 9 Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA Correspondence to: Chuan-Yuan Li, e-mail: Chuan.Li@duke.edu Keywords: necroptosis, RipK1, RipK3, MLKL, tumor growth Received: January 25, 2016 Accepted: February 23, 2016 Published: March 5, 2016 ABSTRACT Necroptotic factors are generally assumed to play a positive role in tumor therapy by eliminating damaged tumor cells. Here we show that, contrary to expectation, necroptotic factors RIPK1, RIPK3, and MLKL promote tumor growth. We demonstrate that genetic knockout of necroptotic genes RIPK1, RIPK3, or MLKL in cancer cells significantly attenuated their abilities to grow in an anchorage-independent manner. In addition, they exhibited significantly enhanced radiosensitivity. The knockout cells also showed greatly reduced ability to form tumors in mice. Moreover, necrosulfonamide (NSA), a previously identified chemical inhibitor of necroptosis, could significantly delay tumor growth in a xenograft model. Mechanistically, we show that necroptoic factors play a significant role in maintaining the activity of NF-κB. Finally, we found that high levels of phosphorylated MLKL in human esophageal and colon cancers are associated with poor overall survival. Taken together, we conclude that pro-necroptic factors such as RIPK1, RIPK3, and MLKL may play a role in supporting tumor growth, and MLKL may be a promising target for cancer treatment.